FDA对注射剂相关控制点与工程实践.pptxVIP

FDA对注射剂相关控制点与工程实践第1页/共77页 2FDA的无菌生产指南Sterile drug manufacturers should have a keen awareness of the public health implication of distributing a nonsterile product. Poor cGMP conditions at a manufacturing facility can ultimately pose a life-theatening health risk to a patientNearly all drugs recalled due to nonsterility or lack of sterility assurance in period spanning 1980-2000 were via aseptic processingIt is a well-accepted principle that sterile drugs should be manufactured using aseptic processing only when terminal sterilization is not feasible第2页/共77页 3无菌产品的质量要求无菌内毒素微粒化学交叉污染灌装量配液的浓度冻干质量(如果是冻干产品)第3页/共77页 4污染源与处理方法污染类别例子来源处理方法Non-viable(粒子等)-金属颗粒-衣服纤维设备, 衣服, 外部空气,水HAVC表面清洁灭菌水纯化Viable(微生物)-细菌-真菌人, 水,外部空气, 设备,器具,API, 赋形剂减少对关键区的干扰HEPA无菌过滤蒸汽灭菌内毒素*-某些细胞壁残骸(常常是水的可生长粒子)湿润的设备或零部件包装容器和封闭件加热的NaOH清洗高温(200度) *一般和空气中的带菌粒子无关第4页/共77页 5关键点 (ISO13408-1)Steps which include handling by personnel of sterile product, immediate or equipment are considered high risk proceduresAny exposure of product to the environment or to a surface is considered a high risk procedure Microbiological risks are frequently influenced by minor faults in handling or equipment design that are not easily recognized.第5页/共77页 6关键点清洁灭菌后产品暴露在环境里的任何操做(传送,灌装, 压塞,冻干进出箱,冻干,扎盖…)清洁与灭菌, 去内毒素和过滤洁净环境人流与物流人(人的卫生,行为,人的数量)水, steam, 洁净空气第6页/共77页 7关键点:人人是洁净车间里的最大污染源:操作人员:衣物,化妆品,头发,皮肤,个人生活方式 (革兰氏阳性菌,葡萄状球菌,棒状杆菌)微生物数( 个)皮肤1000/cm2唾液10,000/ml耳屎100,000/g平稳的活动每小时每人1,000,000人在三分钟里可产生 1,800,000 个粒子第7页/共77页 8FDA最为关心的(这里主要讲与工程实践相关的)设计理念 (QbD)平面布局HVAC监控系统与BMSGMP装修工艺流程 (与工程实践相关的)关键工艺设备PW, WFI, PS洁净气体预防性维护第8页/共77页 9V 模型ValidationURSPQFRSOQDDSIQProcurement,Fabrication,Delivery,Installation,Commissioning第9页/共77页 10设计理念 (QbD)URS起草概念设计平面布局人流物流工艺流功能区级别(核心区,辅助区和普通区)主要设备清单消防初步预算概念设计报告VMP起草第10页/共77页 11设计理念 (QbD)初步设计气流组织图送回风图承载图机械使用点(洁净管道)电气使用点设备布局图HVAC分区(AHU个数)图监控系统层流布局GMP与非GMP装修能量与HVAC风量计算工艺流程设备采购计划项目计划进一步的预算DQ, cGMP符合性评估及风险评估详细工程设计第11页/共77页 12车间的平面布局起草APA 核心区灭菌外清外清配液西林瓶,胶塞,铝盖API更衣更衣人普区过渡区洁净区第12页/共77页 13车间的平面布局房间大小要合理 (足够的空间给消毒灭菌和顺畅的人流和